Suppressor of Cytokine Signaling-1 Peptidomimetic Limits Progression of Diabetic Nephropathy

Abstract

Diabetes is the main cause of CKD and ESRD worldwide. Chronic activation of Janus kinase and signal transducer and activator of transcription (STAT) signaling contributes to diabetic nephropathy by inducing genes involved in leukocyte infiltration, cell proliferation, and extracellular matrix accumulation. This study examined whether a cell-permeable peptide mimicking the kinase-inhibitory region of suppressor of cytokine signaling-1 (SOCS1) regulatory protein protects against nephropathy by suppressing STAT-mediated cell responses to diabetic conditions. In a mouse model combining hyperglycemia and hypercholesterolemia (streptozotocin diabetic, apoE-deficient mice), renal STAT activation status correlated with the severity of nephropathy. Notably, compared with administration of vehicle or mutant inactive peptide, administration of the SOCS1 peptidomimetic at either early or advanced stages of diabetes ameliorated STAT activity and resulted in reduced serum creatinine level, albuminuria, and renal histologic changes (mesangial expansion, tubular injury, and fibrosis) over time. Mice treated with the SOCS1 peptidomimetic also exhibited reduced kidney leukocyte recruitment (T lymphocytes and classic M1 proinflammatory macrophages) and decreased expression levels of proinflammatory and profibrotic markers that were independent of glycemic and lipid changes. In vitro, internalized peptide suppressed STAT activation and target gene expression induced by inflammatory and hyperglycemic conditions, reduced migration and proliferation in mesangial and tubuloepithelial cells, and altered the expression of cytokine-induced macrophage polarization markers. In conclusion, our study identifies SOCS1 mimicking as a feasible therapeutic strategy to halt the onset and progression of renal inflammation and fibrosis in diabetic kidney disease.

The Potential Therapeutic Application of Peptides and Peptidomimetics in Cardiovascular Disease

“…SOCS1-KIR was also shown to be atheroprotective in a type I diabetes mouse model, decreasing vascular plaque accumulation of lipids, macrophages, and T cells, and reducing aorta expression of pro-inflammatory cytokines and chemokines (Recio et al, 2014). More recently, this SOCS1-KIR peptide was demonstrated to further improve diabetes associated-renal damage in mice as well as reduce inflammation and fibrosis in diabetic kidneys (Recio et al, 2016). …”

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

“…Because the relationship between oxidative stress and JAK2/STAT1 pathway is a common mechanism of diabetic tissue damage [20,21], this study aimed to establish the role of SOCS1, one of the most relevant SOCS family members, on redox regulation during development of diabetic complications. Previous animal studies from our group demonstrated that therapeutic targeting of SOCS family prevents tissue injury in both nondiabetic [23][24][25] and diabetic conditions [26][27][28]. Therefore, this work investigates the antioxidant effects of two different SOCS1-based strategies (adenovirus-mediated gene transfer and peptidomimetic of the kinase-inhibitory region) in the setting of diabetic micro-and macrovascular complications.…”

Magnesium lithospermate B improves the gut microbiome and bile acid metabolic profiles in a mouse model of diabetic nephropathy

“…Diabetes mellitus (DM) is one of the most prevalent causes of chronic kidney disease (CKD) [1] and end-stage-renal disease [2]. In the United States,~20-40% of DM patients develop diabetic nephropathy (DN) [3].…”